In Protocol Version 2.0, inclusion and exclusion criteria were modified; dosing and drug supplies text was revised; modifications to laboratory testing (e.g., bilirubin, Heinz bodies, folate, thyroid stimulating homone, and oxygen content) were incorporated; and clarifications and/or modifications to other procedural activities (e.g., informed consent and subject withdrawal, unblinding, Modified ADCS-CGIC evaluations, telephone contacts, ECG assessments, physical and neurological examinations, serotonin toxicity assessments, and blood sample collection and labeling) were also incorporated.

In Protocol Version 3.0, background information was modified to include new reproductive toxicity findings (the discussion of contraceptive measures was also updated accordingly) and clinical pharmacokinetic and safety data; inclusion and exclusion criteria were modified; clarifications and/or modifications to safety assessments and procedures (e.g., dosing and study continuation decisions to be made based on electrocardiogram results, Unified Parkinson’s Disease Rating Scale version, Heinz body determination, serotonin toxicity assessments, pulse rate measurements, and reporting/handling of adverse events of special interest) were incorporated; and clarifications and/or modifications to other assessments and procedural activities were also incorporated.

In Protocol Version 4.0, additional clinical trial sites were added in new countries; an exploratory objective/endpoint was added to evaluate the effect of LMTM as assessed by the change from Baseline on Addenbrooke’s Cognitive Examination-III (ACE-III) to permit comparison of Addenbrooke’s Cognitive Examination-Revised (ACE-R) and ACE-III total scores; an exploratory objective was added to determine the effect of LMTM in subjects with known genetic mutations associated with bvFTD; inclusion and exclusion criteria were modified; instructions for dose interruptions were revised; clarifications and/or modifications to safety assessments and procedures were incorporated; the definitions of serious adverse events and other medically significant events were clarified; clarifications and/or modifications to other assessments and procedural activities were incorporated; and the statistical analysis discussion was revised to incorporate an additional sensitivity analysis, revise the definition of a responder, and indicate that interim analyses may performed.

In Protocol Version 5.0, modifications were incorporated to clarify the presentation of the locations (countries and regions) of participating clinical trial sites; clarify the exclusion criterion regarding current or prior participation in a clinical trial of a product for cognition; allow any suitable laboratory to be used for measurement of glucose-6-phosphate dehydrogenase for deficiency screening; and address comments received from participating Member States in the Voluntary Harmonisation Procedure to restore the exclusionary creatinine clearance to <50 mL/min and to unblind treatment allocation for Suspected Unexpected Serious Adverse Reaction reporting to the pertinent regulatory authorities.

In Protocol Version 6.0, modifications were incorporated to no longer require routine magnetic resonance imaging (MRI) monitoring for evaluation of amyloid related imaging abnormalities based on correspondence received from the United States Food and Drug Administration. Additional modifications were included with regards to concomitant medications and study drug storage temperature conditions.

In Protocol Version 8.0, modifications (relative to Protocol Version 6.0) were incorporated for the clinical efficacy endpoints, imaging endpoints, and statistical analyses in light of newly emerging regulatory guidances and data available from other studies. These modifications were introduced in an interim protocol amendment (Version 7.0 dated 29 June 2015) and were incorporated in the last protocol amendment for this study (Version 8.0). Protocol Version 7.0 was not distributed for implementation at the clinical sites and was superseded by Protocol Version 8.0. The primary, secondary, and exploratory endpoints and statistical analyses were modified as follows: symptomatic effect as reflected by the Functional Activities Questionnaire (FAQ) and disease-modifying effect based on reduction in decline in whole brain volume (WBV) by magnetic resonance imaging (MRI) became primary endpoints, the Modified Alzheimer's Disease Cooperative Study – Clinical Global Impression of Change became a secondary endpoint, and disease modification by reduction in the rate of atrophy in frontal and temporal lobes as well as ventricular volume by MRI imaging was added as an exploratory endpoint. As the Addenbrooke’s Cognitive Examination-III (ACE-III) and Addenbrooke’s Cognitive Examination-Revised (ACE-R) are highly correlated, in the few instances where only ACE-III may have been obtained at Baseline, the change in total score (out of 100) from Baseline ACE-III to subsequent ACE-R was to be used to compute the change in ACE-R. Additional changes from the last implemented protocol included updates to administrative and background information, modifications and clarifications to safety assessments and other procedures including quality assurance and clinical monitoring, as well as other minor revisions to provide further clarification.